Epilepsy is a neurological condition that makes people prone to seizures. A seizure is a change in sensation, awareness, or behavior brought about by a brief electrical disturbance in the brain. Seizures vary from a momentary disruption of the senses, to short periods of unconsciousness or staring spells, to convulsions (Fisher et al., Epilepsia 46: 470-472, 2005). Some people have just one type of seizure. Others have more than one type. All seizures are caused by the same thing: a sudden change in how the cells of the brain send electrical signals to each other.
During epilepsy, a propagation of high frequency, continuous firing is initiated, referred to as a seizure. The severity and symptoms of this seizure will depend on the position of the initial focal point, seizure length, frequency of the discharges and the distance the propagation spreads. Essentially, what a patient experiences during a seizure will depend on where in the brain the epileptic activity begins and how widely and rapidly it spreads. Neurons may fire up to 500 times a second during an epileptic seizure, over six times the normal rate of about 80 times a second. The onset of epilepsy is defined as a condition characterized by recurrent, unprovoked seizures.
There are over 40 different types of seizures, ranging from seizures that go totally unnoticed by others to tonic-clonic seizures which involve muscular contraction, uncontrollable jerks and loss of consciousness. Knowing which type of seizures a person has is useful as this will determine which antiepileptic drug (AED) is most likely to be of benefit. However, the choice of the AED also depends on several other issues, including the age and sex of the patient, requirements for compliance and the presence of hard-to-treat epileptic syndromes. The causes of epilepsy can be divided into three categories:
Symptomatic epilepsy has a known cause, e.g. structural abnormality of the brain, including head trauma, birth trauma, cerebrovascular disorders, cerebral anoxia and brain tumors. Idiopathic epilepsy has no clear underlying cause for the sudden start of the seizures, although it is thought that having a low seizure threshold could be a contributing factor. Cryptogenic epilepsy may be symptomatic or idiopathic. This form of epilepsy is believed to be symptomatic of a hidden cause of unknown etiology, although unlike idiopathic epilepsy, it is not thought to have started due to a low seizure threshold.
Epilepsy is the one of the most common neurological disorders with approximately 3.3 Million patients in North America and almost 200,000 new cases annually (Banerjee et al., Epilepsy Res. 85: 31-45, 2009 and Epilepsy Prevalence, Incidence and Other Statistics (2011).
Since the introduction of barbiturates as the first anticonvulsant therapy there have been many drugs discovered and developed to treat the disorder. However, despite the many therapeutic options available, a large number of patients are refractory to antiepileptic treatments: patients either fail to respond to any drug treatment or have a poor response with continuing seizures.
Currently, treatment of epilepsy is symptom-focused, i.e., to reduce or eliminate seizure response. While many new AEDs have been commercialized in the past 15 years with improved seizure control and reduced side effects, there still remain important unmet medical needs in the treatment of epilepsy. Successful management of epilepsy still remains a significant problem as demonstrated by the fact that despite using various combinations of AEDs, 20-25% of epileptic patients are insensitive to currently available medication. Therefore, there is an ongoing need to discover and develop effective drugs or synergistic combinations of drugs for treating epilepsy.
Following observations that fasting can decrease the incidence of seizures in epilepsy patients, it was hypothesised that this was due to the production of ketones as metabolism switched from carbohydrates to lipids. Although glucose metabolism is the primary source of brain energy, ketone metabolism provides an alternative pathway, which normally occurs under starvation conditions. Ketone bodies are a natural endogenous energy source mainly produced by the liver from mobilisation of endogenous body fat and utilised by extrahepatic tissues (brain, heart, kidney, muscle, etc.).
The ketogenic diet was introduced in the 1920's as a high fat diet which would produce elevated levels of ketone bodies in the plasma (Maalouf et al., Brain Res Rev. 59: 293-315, 2009 and Hartman et al., Pediatr Neurol. 36: 281-292, 2007). The diet proved to be effective in many patients who failed to respond to conventional treatment and has remained a mainstay or adjunctive treatment for drug resistant patients. Investigations indicated that the diet was an effective anti-seizure treatment in animals (Hartman et al., Pediatric Neurol. 36: 281-292, 2007) as well as humans. The diet is, however, unpalatable and failure to adhere to the diet leads to a return or increase in seizures. In addition, the health consequences of a high fat diet for life can be considerable.
Studies have shown that several ketones produced in animals and humans have anti-seizure activity in animal models (Hartman et al., Epilepsia 49: 334-339, 2008 and Likhodii et al., Ann. Neurol. 54:219-226, 2003). Although the anticonvulsant potential of ketones has been well-established, finding a method to translate this activity into a therapy has proven difficult. Typical ketone bodies such as acetone are very short lived and rapidly removed from the body making their use as therapies impractical. Amongst the research in this area are studies showing that specific medium chain fatty acids, such as caprylic acid (octanoic acid), which can be metabolised to ketones have anticonvulsant properties (Chang et al., Neuropharmacology 69: 1-10, 2013). Accordingly, caprylic acid, which is used in a medium chain free fatty acid ketogenic diet, has been shown to have anticonvulsant effects (Wlaz et al., Neuropharmacology 62: 1882-1889, 2012).
Some ketones have demonstrated the ability to potentiate the anticonvulsant activity of some but not all anti-epileptic drugs (Likhodii et al., Ann. Neurol. 54: 219-226, 2003 and Zarnowska et al., Epilepsia 50: 1132-1140, 2009). A similar effect has been observed for caprylic acid (Wlaz et al., Neuropharmacology 62: 1882-1889, 2012).
The same mechanism which leads to anticonvulsant activity may also produce beneficial cognitive effects. For example, caprylic acid supplementation has been shown to significantly improve cognitive performance in Beagle dogs (Pan et al., British Journal of Nutrition 103: 1746-1754, 2010). A similar improvement in cognition following medium chain fatty acids has been reported in diabetic patients (Page et al., Diabetes 58: 1237-1244, 2009). In addition, the cognition enhancing effects for compounds with atypical anticonvulsant activities such as piracetam, aniracetam and the well-used anti-epileptic drug levetiracetam are known (Malykh and Sadaie Drugs 70: 287-312, 2010 and Genton and Vleyman Epileptic Disorders 2: 99-105, 2000).